OBM Transplantation

(ISSN 2577-5820)

OBM Transplantation is an international peer-reviewed Open Access journal, which covers all evidence-based scientific studies related to transplantation, including: transplantation procedures and the maintenance of transplanted tissues or organs; assimilation of grafted tissue and the reconstitution of removed organs or parts of organs; transplantation of heart, lung, kidney, liver, pancreatic islets and bone marrow, etc. Areas related to clinical and experimental transplantation are also of interest.

OBM Transplantation is committed to rapid review and publication, and we aim at serving the international transplant community with high accessibility as well as relevant and high quality content.

We welcome original clinical studies as well as basic science, reviews, short reports/rapid communications, case reports, opinions, technical notes, book reviews as well as letters to the editor. 

Free Publication in 2019
Current Issue: 2019  Archive: 2018 2017
Open Access Review
Respiratory Viral Infections in Lung Transplant Recipients: Implications for Long Term Outcomes and Emerging Therapies

Sheila Krishnan 1, Chadi Hage 2, Raymond Coakley 1, David van Duin 3, Leonard Jason Lobo 1, *

1. University of North Carolina, Division of Pulmonary Diseases and Critical Care, Chapel Hill, North Carolina, USA

2. Indiana University Health Thoracic Transplant Program, Indianapolis, Indiana, USA

3. University of North Carolina, Division of Infectious Disease, Chapel Hill, North Carolina, USA

Correspondence: Leonard Jason Lobo

Academic Editor: Maricar Malinis

Special Issue: Diagnosis and Management of Infections in Solid Organ Transplant Recipients

Received: February 18, 2019 | Accepted: June 02, 2019 | Published: June 10, 2019

OBM Transplantation 2019, Volume 3, Issue 2, doi:10.21926/obm.transplant.1902065

Recommended citation: Krishnan S, Hage C, Coakley R, van Duin D, Lobo LJ. Respiratory Viral Infections in Lung Transplant Recipients: Implications for Long Term Outcomes and Emerging Therapies. OBM Transplantation 2019;3(2):15; doi:10.21926/obm.transplant.1902065.

© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Lung transplant recipients are at greater risk of respiratory viral infections as compared to other solid organ transplant recipients due to constant exposure of the allograft to the external environment. There are no standardized methods for surveillance, prevention, or treatment of these infections despite their association with increased morbidity and mortality. Various studies have linked respiratory viral infections with acute cellular rejection and chronic allograft dysfunction, and emerging data indicates a role in antibody mediated rejection. This paper will review the prevalence and impact of community acquired respiratory viruses in lung transplant recipients, review the evidence linking these viral infections to long term graft dysfunction and rejection, describe existing strategies for surveillance and prevention, and list the currently available, and promising investigational therapies.

Keywords

Respiratory viral infections; lung transplant; implications; emerging therapies

1. Introduction

Despite advancements in lung transplantation, five-year survival for lung transplant recipients remains lower than other solid organ transplant recipients. Chronic lung allograft dysfunction in the form of bronchiolitis obliterans (BOS) is the most common reason for graft failure and death after the first year of transplant [1]. Long term graft and patient survival are limited due to both acute and chronic allograft rejection. This is believed partly to be due to the constant exposure of the graft to the external environment, which places patients at risk for inhalation of potentially harmful environmental agents, including community-acquired respiratory viruses (CARVs).

The CARVs include rhinovirus, bocavirus, coronavirus, respiratory syncytial virus (RSV), adenovirus, parainfluenza viruses (PIV), influenza A and B, and human metapneumovirus (hMPV). Symptomatic infections with most of these viruses can cause immune mediated deleterious effects on lung function [2,3], leading to the development of acute cellular rejection, antibody mediated rejection, and chronic lung allograft dysfunction (CLAD). Despite this clinical impact, among transplant centers there are no standardized guidelines for surveillance or treatment of these infections.

In this paper, we will review the prevalence and impact of community acquired respiratory viruses in lung transplant recipients, review the evidence linking these viral infections to long term graft dysfunction and rejection, describe existing strategies for surveillance and prevention, and list the currently available and promising investigational therapies.

2. Epidemiology

Symptomatic respiratory viral infections are extremely common after lung transplantation, with estimations of 25-60% of lung transplant recipients infected at some point after transplant [4,5,6,7,8,9]. Though some studies have reported increased CARVs within the first year of transplant [8,10] others have reported that patients are affected at similar rates regardless of time post-transplant [5]. There has not been sufficient data to suggest that higher immunosuppression plays a role. Rhinovirus and PIV occur throughout the year while the other CARVs have a seasonal appearance typically in the winter and spring [11,12]. The most common CARVs are the picornaviruses (coxsackievirus, rhinovirus and other enteroviruses) [4,5,11]. Viruses can enter the distal airway by aspiration of upper airway secretions or by direct inhalation from the environment. Viral tropism also impacts location and extension of infection. Infections range from asymptomatic carriage to acute bronchiolitis, pneumonia, and respiratory failure. The clinical presentation varies depending on symptomatic involvement of upper versus lower respiratory system but can also manifest solely as a decline in pulmonary function testing without overt symptoms.

3. Detection

Multiplex, polymerase chain reaction (PCR) methods are currently the preferred test of choice due to simultaneous identification of multiple viruses, rapid results and higher sensitivity compared to direct fluorescent antibody testing and viral culture [12,13]. Specimens are obtained by nasopharyngeal swab or bronchoalveolar lavage (BAL), depending on the patient’s clinical presentation and ability to ascertain the etiology of the patient’s symptoms or PFT decline on nasopharyngeal swab alone versus need for invasive sampling. While surveillance bronchoscopy is commonly performed after lung transplant, the time interval and microbiology and cytological studies performed vary among transplant centers. Furthermore, some centers perform bronchoscopy only if clinically indicated while others may screen for viral infections via nasopharyngeal swab. In a study analyzing over four thousand respiratory samples, Allyn and colleagues found that when compared to other symptomatic and asymptomatic viral infections, viral pneumonia alone increased the risk of CLAD and graft loss [4]. This might suggest that screening detection methods should not be pursued in asymptomatic patients. In contrast, a smaller study by Kumar and colleagues reported that the incidence of CLAD following respiratory viral infections was similar in both symptomatic and asymptomatic patients [12]. These results suggest that screening for viral infections could confer a benefit, possibly in the early post-transplant period when the graft is most vulnerable. Since nasopharyngeal swabs facilitate non-invasive respiratory sampling, a standardized approach would be helpful to guide if and how often to screen. Such an approach would require assessment of the cost of routine testing and opportunity to make a clinically meaningful intervention.

4. Acute Rejection, CLAD, and AMR

A decline in spirometry due to symptomatic lower respiratory tract viral infection that does not progress to chronic graft dysfunction is expected to recover within one to three months [8,14,15,16,17,18]. These transient decreases in lung function are not necessarily related to acute cellular rejection, but when acute rejection is identified in conjunction with a respiratory viral infection, time to recovery of baseline lung function can be prolonged [18].

The pathogenesis of acute cellular rejection (ACR) involves a T cell driven process characterized by mononuclear cell infiltrates around small vessels and/or airways [19]. Respiratory viral infections can trigger ACR through upregulation of cytokines that lead to T cell activation; however, the link between respiratory viral infections and ACR has not been definitively established. There are several studies that have reported an association between CARVs and acute rejection [2,12,20,21,22]. Among these studies, all of the CARVs were associated with acute rejection. Vilchez and colleagues reported pathologic evidence of acute rejection in 82% of patients with PIV infection who underwent transbronchial biopsies [22]. Other studies, including a recent systematic review, have reported absence of an association [5,18,23,24,25,26]. It is significant to note that in the studies that reported an association with ACR, there was a higher number of hMPV infections compared to those that did not. One possibility for the heterogeneous findings is the difference in diagnostic methods used among various studies. As mentioned previously, current methods include molecular diagnostic approaches in the form of PCR which increases the sensitivity of diagnosing respiratory viral infections.

Despite improvements in immunosuppressive regimens and reduction in acute cellular rejection, the incidence of CLAD has remain unchanged. The risk for chronic rejection due to respiratory viral infections could partially explain this, as evidenced by many studies [26,27,28,29]. Table 1 lists the most relevant studies linking respiratory viral infections to allograft dysfunction.

Lung function is not impacted equally by all the CARVs. Some viral pathogens invoke severe and irreversible long-term graft dysfunction as a result of chronic rejection. Depending on the type of virus, the rate of BOS development after CARV infection has been estimated to range from 32-50% [30]. The time between infection and bronchiolitis obliterans can range between 1 and 14 months [22,31,32,33,34]. The Paramyxoviridae family of viruses (which includes RSV, PIV, and hMPV), influenza, and adenovirus can display high virulence in immunocompetent patients, but particularly in lung transplant patients they have been shown to cause acute respiratory failure, BOS, CLAD development, and sometimes death more than the other CARVs [8,20,33,35,36,37,38]. Acute mortality from RSV in lung transplant recipients has been reported to be 10-20% [8,20,34], while the development of CLAD after RSV infection has been estimated to be as high as 38% [20]. Recently Magnusson et al. reported that coronavirus infections that occurred in the first year of lung transplantation were associated with an increased risk for CLAD development [39].

The link between respiratory viral infections and antibody mediated rejection (AMR) is new and emerging. There is no agreed upon histologic definition of AMR, but the pathogenesis involves preformed or de novo circulating antibodies that contribute to both acute and chronic rejection. The International Society for Heart and Lung Transplantation released a consensus report [40] defining and staging AMR that includes deposition of complement product C4d on the capillary endothelium which has been shown to be a surrogate marker for AMR in other solid organ transplants [41,42,43,44]. Immune stimulation by infections can contribute to antibody formation in susceptible patients. In a retrospective analysis, patients who developed RSV infection within 180 days after lung transplant had significantly higher rates of new human leukocyte antigen [45] and new donor specific antibody (DSA) detection [46]. In a separate study 38% of patients developed de novo DSAs after CARV infection which included PIV, RSV, adenovirus, influenza A and B, hMPV, and picornavirus. 11% developed new de novo DSAs after infection, most of which were class II DSAs [47]. Pulmonary AMR is a developing area with many unknowns, but with the recent release of consensus statements on the definition and management [48], it is likely that additional studies will arise to help identify the triggers and mediators of antibody development.

Table 1 Publications documenting an association of community acquired respiratory viral infections and allograft dysfunction.

5. Prevention, Infection Control, and Treatment

There is considerable variability among transplant centers in regard to surveillance and treatment strategies. Education and prevention, on the other hand, are strategies that can be applied by all to protect allograft function given the mounting evidence that CARVs play a role in CLAD development. Education should be provided to patients, family members, caregivers, and healthcare professionals on infection-avoidance behavior and the protective effects of community immunity through vaccination conferred to the immunocompromised patient. Exposure prevention should not be underestimated; avoiding or limiting contact with sick individuals and good hand hygiene are important measures that can be practiced by everyone. Specifically, presenteism, which occurs when healthcare workers go to work despite having a medical illness, is a public health hazard in regard to disease transmission and extension. Healthcare work culture, expectations, and the demands of patient care are factors contributing to this problem.

Once considered or confirmed as a diagnosis, infection control is a vital practice to prevent further transmission and avoid outbreaks. The employment of droplet and contact precautions both during waiting times for test results as well as after confirmed diagnosis are methods for containing infection [50,51]. In cases of outbreaks, other strategies include limiting patient visitors, screening visitors for symptoms of respiratory tract infections, limiting patient transport while diagnostic testing is in process, and moving patients to private rooms.

Primary prophylaxis and vaccinations are the two strategies studied for influenza. Primary prophylaxis can be useful in cases where vaccination is not tolerable or is unavailable. Ison and colleagues evaluated primary prophylaxis with oseltamivir in stem cell, liver, and kidney transplant recipients and found a significant reduction in PCR positive (2.1% versus 8.4%) or culture positive (0.4% versus 3.1%) samples for influenza [52]. Some challenges to adopting this method of prevention include patient concerns regarding pill burden and drug side effects, as well as cost as it relates to insurance coverage for a season long prescription. A separate recent study demonstrated improved influenza vaccine immunogenicity by administering a booster vaccine 4-6 weeks after the initial vaccination in solid organ transplant recipients. After receiving this second dose, recipients had increased seroconversion rates to H1N1 (53.8% versus 37.6%), influenza A (48.1% versus 32.3%), and influenza B (90.7% versus 75%) [53]. In a separate study evaluating high dose versus standard dose flu vaccine administered to solid organ transplant patients, patient who received the high dose demonstrated significantly better immunogenicity, with seroconversions to H1N1, influenza A, and influenza B of 40.5% versus 20.5%, 57.1% versus 32.5%, and 58.3% versus 41.6%, respectively [54]. The benefit of influenza vaccination remains significant even if transplant patients become infected. A recent prospective study evaluating influenza in solid organ transplant recipients, patients who received influenza vaccine in the same season has lower risk of pneumonia and intensive care unit admissions and patients treated with antiviral therapy within 48 hours had better outcomes [55]. Unfortunately, there are no approved vaccinations for the other CARVs. Palivizumab is a monoclonal antibody that is approved for use only in high risk infants for RSV prevention but has rarely been used in thoracic lung transplant recipients with RSV [56].

Similar to the management of non-influenza viral infections in immunocompetent patients, the mainstay of treatment in solid organ transplant recipients is supportive care; however, there is some supportive data showing that treatment of paramyxoviruses results in less risk of BOS or reduced BOS severity. Table 2 lists the existing studies and outcomes of treatment in regard to graft function, not mortality. Most of the studies have looked at outcomes in RSV treatment, with smaller numbers of studies evaluating treatment of hMPV and PIV infections. Below are the emerging or investigational treatments for some of the respiratory viral infections.

Table 2 Publications evaluating effect of antiviral therapy and graft function.

6. RSV

Treatment strategies vary among centers in regard to treating lower versus upper respiratory tract RSV infections, the route and dose of antiviral agent, and adjunct therapies such as steroids or intravenous immunoglobulin (IVIG) [60]. Many studies have shown benefit of ribavirin in both inhaled and oral route [15,58,59], though inhaled ribavirin is significantly more expensive and poses teratogenic risk to pregnant caregivers, and therefore may influence trends in practice. A recent retrospective study and review showed that oral ribavirin was a safe and cost-effective alternative to inhaled ribavirin without any difference in clinical outcomes [57].

Ongoing investigational therapies for RSV include RNA interference drugs and fusion inhibitors [61]. A recent promising phase 2b study evaluating the impact of drug ALN-RSV01, an interfering RNA, demonstrated reduced incidence of BOS in lung transplant patients after RSV infection [35]. Other investigational drugs that inhibit viral replication and viral entry into cells have been shown in healthy adults inoculated with RSV to result in more rapid RSV clearance and greater reduction in viral load [62,63]. Presatovir is a promising fusion inhibitor that demonstrated a reduction in viral load in HCT patients. In the hopes of finding the same results in lung transplant patients, Gottlieb and colleagues conducted a double-blind randomized trial in 77 patients and unfortunately did not see any reduction in viral load, clinical improvement, or change in lung function [35].

7. Parainfluenza

Experimental therapies to treat parainfluenza virus have been underway, though nothing has yet been approved for use. These have included host-directed therapies as opposed to a pathogen-targeted approach. In a single arm clinical trial in HCT patients, use of a sialidase protein that inhibits viral attachment to host cells improved the clinical outcome either completely or partially in 13 out of 16 patients [64].

8. Influenza

Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) have been proven to be effective at decreasing flu severity and duration of symptoms [65,66]. This year a new flu antiviral medicine, baloxavir, was approved by FDA. Unlike the neuraminidase inhibitors, baloxavir interferes with RNA transcription, thereby inhibiting viral replication. In the phase III trial baloxavir was not only associated with faster recovery and reduced risk of complications in high risk patients, but it was also superior to oseltamivir in reducing duration of viral replication and in resolving influenza B illness [67,68]. Potential limitations include development of influenza virus variants with reduced susceptibility after a single dose [69,70], thereby making it difficult to determine if viral detection after treatment is due to viral shedding or persistent infection. Studies looking at adjunct therapy with other antivirals have not shown any clinical benefit [71]. A phase 3 study is underway to evaluate immune plasma as a treatment for influenza. In the results published from the open label phase 2 trial, patients who were hospitalized with severe infection had a trend toward improved respiratory status and overall mortality [72].

9. Adenovirus

In lung transplant recipients, adenovirus found in the lung has been shown to cause graft failure and even death [32,49]. Less is known about adenovirus viremia; however, one study suggests that viremia in lung transplant recipients is more common than initially thought, but that in low levels does not contribute to lung allograft dysfunction [73]. The limited data on antiviral therapy for adenovirus comes from hematopoietic cell transplant (HCT) recipients. Cidofovir is used off-label, with some benefit shown in case series and not from controlled studies. High peripheral blood viral loads correlate with disseminated infections and can be used to clinically to assess response to therapy [74,75]. Nephrotoxicity is a common complication that often limits use. Brincidofovir is a derivative of cidofovir without the associated myelotoxicity or nephrotoxic effects. There have been two clinical trials looking at brincidofovir in allogeneic HCT patients which have demonstrated improved survival in patients who sustained a virologic response, including those who were highly immunosuppressed with CD4 counts less than 50 cells/µl [76,77]. There are ongoing trials evaluating the use of adenovirus-specific cytotoxic T-lymphocytes.

10. Conclusions

Respiratory viral infections after lung transplantation are common and have been linked to graft dysfunction through acute cellular rejection, CLAD, and more recently antibody mediated rejection. Through these mechanisms they contribute to significant morbidity and mortality in lung transplant recipients, thereby limiting long-term survival. Though generally limited in treatment, there are emerging therapies that are promising to decrease the incidence of BOS after infection. Further investigation and randomized trials are needed to determine the pathogenesis and optimal treatment for respiratory viral infections so that lung transplant centers can achieve an effective standardized approach in management of CARVs.

Author Contributions

Conception and design:  All authors (SK, CH, RC, DvD, LJL) contributed to conceptualization and article design.

Administrative support:  N/A.

Provision of study materials or patients: N/A

Collection and assembly of data: SK primarily performed pertinent literature searches for data compilation.

Data analysis and interpretation: N/A.

Manuscript writing:  All authors (SK, CH, RC, DvD, LJL) were responsible for writing and editing of the manuscript.

Final approval of manuscript: All authors (SK, CH, RC, DvD, LJL) gave final approval of manuscript prior to submission.

Competing Interests

The authors have declared that no competing interests exist.

References

  1. Kulkarni HS, Cherikh WS, Chambers DC, Garcia VC, Hachem RR, Kreisel D, et al. Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis. J Heart Lung Transplant. 2019; 38: 5-16. [CrossRef]
  2. Kumar D, Erdman D, Keshavjee S, Peret T, Tellier R, Hadjiliadis D, et al. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant. 2005; 5: 2031-2036. [CrossRef]
  3. Weigt SS, Derhovanessian A, Liao E, Hu S, Gregson AL, Kubak BM, et al. CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction. Am J Transplant. 2012; 12: 477-484. [CrossRef]
  4. Allyn PR, Duffy EL, Humphries RM, Injean P, Weigt SS, Saggar R, et al. Graft loss and CLAD-onset is hastened by viral pneumonia after lung transplantation. Transplantation. 2016; 100: 2424-2431. [CrossRef]
  5. Bridevaux PO, Aubert JD, Soccal PM, Mazza-Stalder J, Berutto C, Rochat T, et al. Incidence and outcomes of respiratory viral infections in lung transplant recipients: A prospective study. Thorax. 2014; 69: 32-38. [CrossRef]
  6. de Lima CR, Mirandolli TB, Carneiro LC, Tusset C, Romer CM, Andreolla HF, et al. Prolonged respiratory viral shedding in transplant patients. Transplant Infect Dis. 2014; 16: 165-169. [CrossRef]
  7. Garbino J, Gerbase MW, Wunderli W, Deffernez C, Thomas Y, Rochat T, et al. Lower respiratory viral illnesses: Improved diagnosis by molecular methods and clinical impact. Am J Resp Crit Care Med. 2004; 170: 1197-1203. [CrossRef]
  8. McCurdy LH, Milstone A, Dummer S. Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin. J Heart Lung Transplant. 2003; 22: 745-753. [CrossRef]
  9. Peghin M, Hirsch HH, Len O, Codina G, Berastegui C, Saez B, et al. Epidemiology and immediate indirect effects of respiratory viruses in lung transplant recipients: A 5-year prospective study. Am J Transplant. 2017; 17: 1304-1312. [CrossRef]
  10. Weinberg A, Lyu DM, Li S, Marquesen J, Zamora MR. Incidence and morbidity of human metapneumovirus and other community-acquired respiratory viruses in lung transplant recipients. Transplant Infect Dis. 2010; 12: 330-335. [CrossRef]
  11. Billings JL, Hertz MI, Wendt CH. Community respiratory virus infections following lung transplantation. Transplant Infect Dis. 2001; 3: 138-148. [CrossRef]
  12. Kumar D, Husain S, Chen MH, Moussa G, Himsworth D, Manuel O, et al. A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients. Transplantation. 2010; 89: 1028-1033. [CrossRef]
  13. Mahony J, Chong S, Merante F, Yaghoubian S, Sinha T, Lisle C, et al. Development of a respiratory virus panel test for detection of twenty human respiratory viruses by use of multiplex PCR and a fluid microbead-based assay. J Clin Microbiol. 2007; 45: 2965-2970. [CrossRef]
  14. Burrows FS, Carlos LM, Benzimra M, Marriott DJ, Havryk AP, Plit ML, et al. Oral ribavirin for respiratory syncytial virus infection after lung transplantation: Efficacy and cost-efficiency. J Heart Lung Transplant. 2015; 34: 958-962. [CrossRef]
  15. Fuehner T, Dierich M, Duesberg C, DeWall C, Welte T, Haverich A, et al. Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections. Antivir Ther. 2011; 16: 733-740. [CrossRef]
  16. Glanville AR, Scott AI, Morton JM, Aboyoun CL, Plit ML, Carter IW, et al. Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant. 2005; 24: 2114-2119. [CrossRef]
  17. Niggli F, Huber LC, Benden C, Schuurmans MM. Human metapneumovirus in lung transplant recipients: Characteristics and outcomes. Infect Dis. 2016; 48: 852-856. [CrossRef]
  18. Soccal PM, Aubert JD, Bridevaux PO, Garbino J, Thomas Y, Rochat T, et al. Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients. Clin Infect Dis. 2010; 51: 163-170. [CrossRef]
  19. Roden AC, Aisner DL, Allen TC, Aubry MC, Barrios RJ, Beasley MB, et al. Diagnosis of acute cellular rejection and antibody-mediated rejection on lung transplant biopsies: A perspective from members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2017; 141: 437-444. [CrossRef]
  20. Hopkins P, McNeil K, Kermeen F, Musk M, McQueen E, Mackay I, et al. Human metapneumovirus in lung transplant recipients and comparison to respiratory syncytial virus. Am J Resp Crit Care Med. 2008; 178: 876-881. [CrossRef]
  21. Larcher C, Geltner C, Fischer H, Nachbaur D, Muller LC, Huemer HP. Human metapneumovirus infection in lung transplant recipients: clinical presentation and epidemiology. J Heart Lung Transplant. 2005; 24: 1891-1901. [CrossRef]
  22. Vilchez RA, McCurry K, Dauber J, Iacono A, Keenan R, Zeevi A, et al. The epidemiology of parainfluenza virus infection in lung transplant recipients. Clin Infect Dis. 2001; 33: 2004-2008. [CrossRef]
  23. Shah PD, McDyer JF. Viral infections in lung transplant recipients. Semin Resp Crit Care Med. 2010; 31: 243-254. [CrossRef]
  24. Shalhoub S, Husain S. Community-acquired respiratory viral infections in lung transplant recipients. Curr Opin Infect Dis. 2013; 26: 302-308. [CrossRef]
  25. Vu DL, Bridevaux PO, Aubert JD, Soccal PM, Kaiser L. Respiratory viruses in lung transplant recipients: a critical review and pooled analysis of clinical studies. Am J Transplant. 2011; 11: 1071-1078. [CrossRef]
  26. Sayah DM, Koff JL, Leard LE, Hays SR, Golden JA, Singer JP. Rhinovirus and other respiratory viruses exert different effects on lung allograft function that are not mediated through acute rejection. Clin Transplant. 2013; 27: E64-E71. [CrossRef]
  27. Fisher CE, Preiksaitis CM, Lease ED, Edelman J, Kirby KA, Leisenring WM, et al. Symptomatic respiratory virus infection and chronic lung allograft dysfunction. Clin Infect Dis. 2016; 62: 313-319. [CrossRef]
  28. Gottlieb J, Schulz TF, Welte T, Fuehner T, Dierich M, Simon AR, et al. Community-acquired respiratory viral infections in lung transplant recipients: A single season cohort study. Transplantation. 2009; 87: 1530-1537. [CrossRef]
  29. Magnusson J, Westin J, Andersson LM, Brittain-Long R, Riise GC. The impact of viral respiratory tract infections on long-term morbidity and mortality following lung transplantation: A retrospective cohort study using a multiplex PCR panel. Transplantation. 2013; 95: 383-388. [CrossRef]
  30. Vilchez RA, Dauber J, Kusne S. Infectious etiology of bronchiolitis obliterans: The respiratory viruses connection - myth or reality? Am J Transplant. 2003; 3: 245-249. [CrossRef]
  31. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant. 2002; 21: 559-566. [CrossRef]
  32. Bridges ND, Spray TL, Collins MH, Bowles NE, Towbin JA. Adenovirus infection in the lung results in graft failure after lung transplantation. J Thorac Cardiov Surg. 1998; 116: 617-623. [CrossRef]
  33. Garantziotis S, Howell DN, McAdams HP, Davis RD, Henshaw NG, Palmer SM. Influenza pneumonia in lung transplant recipients: Clinical features and association with bronchiolitis obliterans syndrome. Chest. 2001; 119: 1277-1280. [CrossRef]
  34. Palmer SM, Jr., Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VF. Community respiratory viral infection in adult lung transplant recipients. Chest. 1998; 113: 944-950. [CrossRef]
  35. Gottlieb J, Zamora MR, Hodges T, Musk AW, Sommerwerk U, Dilling D, et al. ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients. J Heart Lung Transplant. 2016; 35: 213-221. [CrossRef]
  36. Vilchez RA, Dauber J, McCurry K, Iacono A, Kusne S. Parainfluenza virus infection in adult lung transplant recipients: An emergent clinical syndrome with implications on allograft function. Am J Transplant. 2003; 3: 116-120. [CrossRef]
  37. Ng BJ, Glanville AR, Snell G, Musk M, Holmes M, Chambers DC, et al. The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients. Am J Transplant. 2011; 11: 568-574. [CrossRef]
  38. Schuurmans MM, Isenring BD, Jungo C, Boeni J, Mueller NJ, Kohler M, et al. Clinical features and outcomes of influenza infections in lung transplant recipients: A single-season cohort study. Transplant Infect Dis. 2014; 16: 430-439. [CrossRef]
  39. Magnusson J, Westin J, Andersson LM, Lindh M, Brittain-Long R, Norden R, et al. Viral respiratory tract infection during the first postoperative year is a risk factor for chronic rejection after lung transplantation. Transplant Direct. 2018; 4: e370. [CrossRef]
  40. Levine DJ, Glanville AR, Aboyoun C, Belperio J, Benden C, Berry GJ, et al. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2016; 35: 397-406. [CrossRef]
  41. Fedson SE, Daniel SS, Husain AN. Immunohistochemistry staining of C4d to diagnose antibody-mediated rejection in cardiac transplantation. J Heart Lung Transplant. 2008; 27: 372-379. [CrossRef]
  42. Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, Tolkoff-Rubin NE, et al. Chronic humoral rejection: Identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol. 2001; 12: 574-582.
  43. Rodriguez ER, Skojec DV, Tan CD, Zachary AA, Kasper EK, Conte JV, et al. Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers. Am J Transplant. 2005; 5: 2778-2785. [CrossRef]
  44. Demetris AJ, Bellamy C, Hubscher SG, O'Leary J, Randhawa PS, Feng S, et al. 2016 comprehensive update of the banff working group on liver allograft pathology: Introduction of antibody-mediated rejection. Am J Transplant. 2016; 16: 2816-2835. [CrossRef]
  45. Eberlein M, Permutt S, Chahla MF, Bolukbas S, Nathan SD, Shlobin OA, et al. Lung size mismatch in bilateral lung transplantation is associated with allograft function and bronchiolitis obliterans syndrome. Chest. 2012; 141: 451-460. [CrossRef]
  46. Permpalung N, Thaniyavarn T, Saullo J, Arif S, Miller R, Reynolds J, et al. Rejection outcomes in lung transplant recipients post respiratory syncytial virus infections. Infect Dis Week. 2018. [CrossRef]
  47. Ainge-Allen HW, Benzimra M, Havryk AP, Rigby AL, Malouf MA, Plit ML, et al. The development of De Novo donor specific antibodies following community acquired respiratory virus infection after lung transplantation: A novel association. J Heart Lung Transplant. 2014; 33: S159-S160. [CrossRef]
  48. Roux A, Levine DJ, Zeevi A, Hachem R, Halloran K, Halloran PF, et al. Banff lung report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR). Am J Transplant. 2019; 19: 21-31. [CrossRef]
  49. Khalifah AP, Hachem RR, Chakinala MM, Schechtman KB, Patterson GA, Schuster DP, et al. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Resp Crit Care Med. 2004; 170: 181-187. [CrossRef]
  50. WHO Guidelines Approved by the Guidelines Review Committee. Infection prevention and control of epidemic- and pandemic-prone acute respiratory infections in health care. Geneva: World Health Organization Copyright (c) World Health Organization 2014.; 2014.
  51. Prevention CfDCa. Healthcare Infection Control Practices Advisory Committee (HICPAC). Available at: https://wwwcdcgov/hicpac/2007IP/2007ip_appendAhtml. 2007.
  52. Ison MG. Antiviral therapies for respiratory viral infections in lung transplant patients. Antivir Ther. 2012; 17: 193-200. [CrossRef]
  53. Cordero E, Roca-Oporto C, Bulnes-Ramos A, Aydillo T, Gavalda J, Moreno A, et al. Two doses of inactivated influenza vaccine improve immune response in solid organ transplant recipients: Results of TRANSGRIPE 1-2, a randomized controlled clinical trial. Clin Infect Dis. 2017; 64: 829-838. [CrossRef]
  54. Natori Y, Shiotsuka M, Slomovic J, Hoschler K, Ferreira V, Ashton P, et al. A double-blind, randomized trial of high-dose vs standard-dose influenza vaccine in adult solid-organ transplant recipients. Clin Infect Dis. 2018; 66: 1698-1704. [CrossRef]
  55. Kumar D, Ferreira VH, Blumberg E, Silveira F, Cordero E, Perez-Romero P, et al. A 5-year prospective multicenter evaluation of influenza infection in transplant recipients. Clin Infect Dis. 2018; 67: 1322-1329. [CrossRef]
  56. Liu V, Dhillon GS, Weill D. A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients. Transplant Infect Dis. 2010; 12: 38-44. [CrossRef]
  57. Trang TP, Whalen M, Hilts-Horeczko A, Doernberg SB, Liu C. Comparative effectiveness of aerosolized versus oral ribavirin for the treatment of respiratory syncytial virus infections: A single-center retrospective cohort study and review of the literature. Transplant Infect Dis. 2018; 20: e12844. [CrossRef]
  58. Li L, Avery R, Budev M, Mossad S, Danziger-Isakov L. Oral versus inhaled ribavirin therapy for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant. 2012; 31: 839-844. [CrossRef]
  59. Pelaez A, Lyon GM, Force SD, Ramirez AM, Neujahr DC, Foster M, et al. Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant. 2009; 28: 67-71. [CrossRef]
  60. Beaird OE, Freifeld A, Ison MG, Lawrence SJ, Theodoropoulos N, Clark NM, et al. Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: A survey of institutions in the Midwestern Respiratory Virus Collaborative. Transplant Infect Dis. 2016; 18: 210-215. [CrossRef]
  61. Zamora MR, Budev M, Rolfe M, Gottlieb J, Humar A, Devincenzo J, et al. RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Resp Crit Care Med. 2011; 183: 531-538. [CrossRef]
  62. DeVincenzo JP, McClure MW, Symons JA, Fathi H, Westland C, Chanda S, et al. Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. New Engl J Med. 2015; 373: 2048-2058. [CrossRef]
  63. DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E, et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. New Engl J Med. 2014; 371: 711-722. [CrossRef]
  64. Salvatore M, Satlin MJ, Jacobs SE, Jenkins SG, Schuetz AN, Moss RB, et al. DAS181 for treatment of parainfluenza virus infections in hematopoietic stem cell transplant recipients at a single center. Biol Blood Marrow Transplant. 2016; 22: 965-970. [CrossRef]
  65. Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: Systematic review and meta-analyses of randomised controlled trials. BMJ. 2003; 326: 1235. [CrossRef]
  66. Moscona A. Neuraminidase inhibitors for influenza. New Engl J Med. 2005; 353: 1363-1373. [CrossRef]
  67. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. New Engl J Med. 2018; 379: 913-923. [CrossRef]
  68. Ison MG, Portsmouth S, Yoshida Y, Shishido T, Hayden FG, Uehara T. Phase 3 trial of baloxavir marboxil in high risk influenza patients (CAPSTONE-2 study). Infect Dis Week. 2018. [CrossRef]
  69. Gubareva LV, Mishin VP, Patel MC, Chesnokov A, Nguyen HT, De La Cruz J, et al. Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons. Euro Surveill. 2019; 24: 1800666. [CrossRef]
  70. Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. 2018; 8: 9633. [CrossRef]
  71. Beigel JH, Bao Y, Beeler J, Manosuthi W, Slandzicki A, Dar SM, et al. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: A multicentre, double-blind, randomised phase 2 trial. Lancet Infect Dis. 2017; 17: 1255-1265. [CrossRef]
  72. Beigel JH, Tebas P, Elie-Turenne MC, Bajwa E, Bell TE, Cairns CB, et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Resp Med. 2017; 5: 500-511. [CrossRef]
  73. Humar A, Doucette K, Kumar D, Pang XL, Lien D, Jackson K, et al. Assessment of adenovirus infection in adult lung transplant recipients using molecular surveillance. J Heart Lung Transplant. 2006; 25: 1441-1446. [CrossRef]
  74. Ganzenmueller T, Buchholz S, Harste G, Dammann E, Trenschel R, Heim A. High lethality of human adenovirus disease in adult allogeneic stem cell transplant recipients with high adenoviral blood load. J Clin Virol. 2011; 52: 55-59. [CrossRef]
  75. Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010; 116: 5476-5485. [CrossRef]
  76. Grimley MS, Chemaly RF, Englund JA, Kurtzberg J, Chittick G, Brundage TM, et al. Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult allogeneic hematopoietic cell transplant recipients: A randomized placebo-controlled phase ii trial. Biol Blood Marrow Transplant. 2017; 23: 512-521. [CrossRef]
  77. Prasad VK, Papanicolaou GA, Maron GM, Vainorious E, Brundage TM, Chittick G, et al. Treatment of Adenovirus (AdV) infection in allogeneic hematopoietic cell transplant (allo HCT) patients (pts) with brincidofovir: Final 36 week results from the advise trial. Biol Blood Marrow Transplant. 2017; 23: 57-58. [CrossRef]
Newsletter
Download PDF

TOP